AB1247 RATIONALE AND DESIGN FOR PODAGRA II: A MULTICENTER RANDOMIZED PHASE 2/3 STUDY ASSESSING THE EFFICACY AND SAFETY OF DAPANSUTRILE, AN ORALLY ADMINISTERED SPECIFIC INHIBITOR OF THE NLRP3 INFLAMMASOME IN SUBJECTS WITH AN ACUTE GOUT FLARE
Authors: T. Jansen, P. Piscitelli, C. Barrow, K. Vought, A. Poshusta, H. Kapushoc, A. Leonard-Segal, M. Noor, D. Skouras, C. Dinarello, N. Schlesinger
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> The formation of the NOD-, LRR-, and pyrin-containing 3 (NLRP3) inflammasome plays a critical role in the initiation of the inflammatory reaction induced by the monosodium urate (MSU) crystals in an acute gout flare. Once assembled, the NLRP3 inflammasome converts pro-interleukin-1β into its active form and initiates IL-1β-dependent inflammation. NLRP3 activation, therefore, occurs upstream of IL-1β, the pivotal cytokine in gouty inflammation and the causative agent mediating symptoms of acute gout flares, including joint pain. Monoclonal antibodies against IL-1β can decrease inflammation and gout flares by neutralizing cicrulating IL-1β and shutting down the IL-1β-mediated inflammatory cascade. However, they must be injected and are associated with immune suppression and increased risk of infection. There remains an unmet need for an orally administered treatment for acute gout flare to safely reduce IL-1β-mediated inflammatory pain without the risk of immunosuppression. In an initial dose-range finding study, PODAGRA I, we reported preliminary evidence of efficacy and safety in this setting with dapansutrile, an orally administered specific inhibitor of the NLRP3 inflammasome. <h3>Objectives</h3> PODAGRA II study is designed to further evaluate the effects of dapansutrile on reducing joint pain and IL-1β-dependent inflammation during acute gout flare. <h3>Methods</h3> The study (NCT05658575/EudraCT 2019-002717-19) is a multicenter, placebo-controlled, prospective, randomized, double-blind trial conducted in the Netherlands, Spain, France, and the USA. A total of 300 patients with acute symptomatic gout flare are being randomized centrally to receive either dapansutrile (2000 mg loading dose followed by 1000 mg BID) or matching placebo tablets for 7 days (2:1 ratio dapansutrile: placebo). The study is designed to determine the superiority of dapansutrile compared to placebo on the symptoms and signs of an acute gout flare. The primary endpoint is the subject-reported pain intensity score in the target joint (evaluated on a 100-mm visual analogue scale) at 72 hours. Secondary endpoints include patient- and investigator-assessment of response to treatment and the investigator-assessed scores for joint tenderness, swelling, erythema, warmth, and range of motion. A subject-assessed quality-of-life questionnaire will be collected, and biomarkers associated with acute gout inflammation (IL-1 β, IL-6 and CRP) will be evaluated. In order to demonstrate both statistical and clinical significance, approximately 170 and 85 evaluable subjects are needed in the dapansutrile and placebo arms, respectively. This assumes a one-sided significance level of α = 0.025, 85% power (1-β), a standard deviation of 25 points, an expected mean difference (Δ=10 points) plus an additional clinical significance of (δ=10 points). To account for dropouts and non-evaluable subjects, up to 200 subjects in the dapansutrile arm, and up to 100 in the placebo arm will be randomized. <h3>Results</h3> The trial has launched and is currently enrolling subjects. <h3>Conclusion</h3> There is a need for an orally administered, safe, and well-tolerated treatment for acute gout flares. PODAGRA II will be the first placebo-controlled, adequately powered, large, multi-center study with an oral NLRP3-specific inhibitor. As gout is a prototypical disease of NLRP3 activation, this trial will provide important new data on NLRP3 inhibition leading to a reduction in joint pain and associated inflammatory biomarkers in acute gout flare. <h3>Reference</h3> [1]Klück V, Jansen TLTA, Janssen M, et al. Dapansutrile, an oral selective NLRP3 inflammasome inhibitor, for treatment of gout flares: an open-label, dose-adaptive, proof-of-concept, phase 2a trial. Lancet Rheumatol. 2020 May;2(5) <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> Tim Jansen Consultant of: AstraZeneca, Abbvie, Olatec Therapeutics, Grant/research support from: Olatec Therapeutics, Phil Piscitelli Shareholder of: Olatec Therapeutics, Employee of: Olatec Therapeutics, Cynthia Barrow Shareholder of: Olatec Therapeutics, Employee of: Olatec Therapeutics, Kip Vought Shareholder of: Olatec Therapeutics, Consultant of: Olatec Therapeutics, Amy Poshusta Shareholder of: Olatec Therapeutics, Consultant of: Olatec Therapeutics, Heather Kapushoc Consultant of: Olatec Therapeutics, Andrea Leonard-Segal Consultant of: Olatec Therapeutics, Mustafa Noor Shareholder of: Olatec Therapeutics, Employee of: Olatec Therapeutics, Damaris Skouras Shareholder of: Olatec Therapeutics, Employee of: Olatec Therapeutics, Charles Dinarello Speakers bureau: Novartis, Amgen, Kinikisa, Paid instructor for: Novartis, Amgen, Kiniksa, Olatec, Consultant of: Olatec, Grant/research support from: Olatec, Naomi Schlesinger Consultant of: Novartis, Horizon, LG Chem, ANI, Protalix. Olatec Therapeutics.